Derivatives of pyrido[2,3-d]pyrimidine, the preparation thereof, and the therapeutic application of the same

ABSTRACT

The invention relates to derivatives of pyrido[2,3-d]pyrimidine, to the preparation thereof, and to the therapeutic application of the same.

The present invention relates to pyrido[2,3-d]pyrimidine derivatives, tothe preparation thereof and to the therapeutic use thereof.

Compounds derived from pyrido[2,3-d]pyrimidine are described in patentapplications WO 01/55 147 and WO 03/000 011 and in patents EP-B-790 997and U.S. Pat. No. 5,733,913. These compounds are potentially useful fortreating cell proliferation conditions.

Thus, and according to a first aspect, a subject of the presentinvention is compounds corresponding to formula (I):

in which:

-   -   R₁ is selected from a group comprising (C₁-C₆)alkyl,        (C₁-C₆)alkyl(C₃-C₇)cycloalkyl, CH₂COR₃, phenyl, or phenyl        substituted with hydroxyl and/or halogen and/or (C₁-C₆)alkyl;    -   R₃ is a hydroxyl, (C₁-C₄)alkoxy, amino, (C₁-C₄)alkylamino or        di(C₁-C₄)alkylamino group;    -   Ar₁ is a radical selected from:

-   -   in which X is O or S, Y is CH₂ or NH, and R₂ is selected from        the group comprising H, (C₁-C₆)alkyl or (CH₂)_(n)NR₄R₅, and R′₂        is (CH₂)_(n)NR₄R₅;    -   R₄ and R₅ are each, independently of one another, a substituent        selected from H, (C₁-C₄)alkyl, (C₁-C₆)alkyl(C₃-C₇)cycloalkyl,        (C₃-C₇)cycloalkyl, C(═NH)NH₂ and SO₂(C₁-C₆)alkyl, R₅ can also be        a CO—(C₁-C₄)alkyl, CO—(C₃-C₇)cycloalkyl, CO-aryl, SO₂-aryl,        tert-butoxycarbonyl or benzyloxycarbonyl group;    -   or R₄ and R₅, together with the nitrogen atom to which they are        attached, constitute an azetidinyl, pyrrolidinyl, piperidinyl,        piperazinyl or morpholinyl radical, said radical being        unsubstituted or substituted one or more times with a        (C₁-C₆)alkyl, (C₁-C₄)alkyl-OH or COO(C₁-C₆)alkyl group;    -   Ar₂ is a phenyl group which is unsubstituted or substituted from        1 to 5 times with similar or different substituents selected        from a halogen atom, a (C₁-C₄)alkyl group, a trifluoromethyl        group or a (C₁-C₄)alkoxy group;    -   n is 1, 2 or 3.

According to a preferred variant, the compounds of formula (I) have asubstituent Ar₁ which is a radical selected from:

-   -   in which R₂ is CH₃ or (CH₂)_(n)NR₄R₅, and R′₂ is CH₂NR₄R₅, in        which R₄ and R₅ are independently selected from H and        (C₁-C₆)alkyl and Y is CH₂ or NH.

The products according to the invention advantageously have asubstituent Ar₂ which is a radical:

in which each R₆, R₇ is independently selected from the group comprisingH, CH₃, OCH₃, F, Cl, Br. R₆ and R₇ are advantageously in the 2- and6-position.

The products according to the invention advantageously have asubstituent Ar₂ selected from phenyl, 2-methoxyphenyl,2,6-dichlorophenyl, 3,5-dimethoxyphenyl, 3,4-dimethoxyphenyl,2,6-dibromophenyl, 2-bromo-6-chlorophenyl, 2,4-dichlorophenyl,3,5-dichlorophenyl, 2,6-dimethylphenyl and 2,6-difluorophenyl.

According to a preferred variant, the compounds of formula (I) have asubstituent Ar₁ which is a radical selected from

A compound that is more particularly preferred according to theinvention is:

(N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)urea)

The compounds of the examples which follow are a subject of the presentinvention.

A compound in accordance with the invention can (i) be in a non-chiralform, or a racemic form, or a form enriched in one stereoisomer, orenriched in one enantiomer; (ii) be optionally salified, and (iii) beoptionally hydrated or solvated.

The compounds of formula (I) can contain one or more asymmetrical carbonatoms.

They can therefore exist in the form of enantiomers or ofdiastereoisomers. These enantiomers and diastereoisomers and alsomixtures thereof, including racemic mixtures, are part of the invention.

The compounds of formula (I) can exist in the form of bases or ofaddition salts with acids. When compounds of formula (I) contain freeacid functions, for example carboxylic, sulphonic or phosphonic, theseacid functions can be salified using bases so as to form addition salts.Such addition salts are part of the invention.

The addition salts with acids or with bases are advantageously preparedwith, respectively, pharmaceutically acceptable acids or bases, but thesalts of other acids or of bases that are useful, for example, for thepurification or the isolation of the compounds of formula (I) are alsopart of the invention.

The compounds of formula (I) can also exist in the form of hydrates orof solvates, i.e. in the form of associations or of combinations withone or more molecules of water or with a solvent. Such hydrates andsolvates are also part of the invention.

In the context of the present invention:

-   -   the term “a halogen atom” is intended to mean: a fluorine, a        chlorine, a bromine or an iodine;    -   the term “an alkyl group” is intended to mean: a linear or        branched, saturated aliphatic group. By way of example, mention        may be made of methyl, ethyl, n-propyl, n-butyl, n-pentyl,        n-hexyl, n-heptyl, 1-methylethyl, 1-methylpropyl,        2-methylpropyl, 1,1-dimethylethyl, 1-methylbutyl, 2-methylbutyl,        3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,        2,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,        3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl,        1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl,        2,3-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl,        1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl,        1-ethyl-2-methylpropyl, 1-ethylbutyl, 2-ethylbutyl,        1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl,        5-methylhexyl, 1,1-dimethylpentyl, 1,2-dimethylpentyl,        1,3-dimethylpentyl, 1,4-dimethylpentyl, 2,2-dimethylpentyl,        2,3-dimethylpentyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl,        3,4-dimethylpentyl, 4,4-dimethylpentyl, 1,1,2-trimethylbutyl,        1,1,3-trimethylbutyl, 1,2,2-trimethylbutyl,        1,2,3-trimethylbutyl, 1,3,3-trimethylbutyl,        2,2,3-trimethylbutyl, 2,3,3-trimethylbutyl,        1,1,2,2-tetramethylpropyl, 1-ethylpentyl, 2-ethylpentyl,        3-ethylpentyl, 1-ethyl-1-methylbutyl, 1-ethyl-2-methylbutyl,        1-ethyl-3-methylbutyl, 2-ethyl-1-methylbutyl,        2-ethyl-2-methylbutyl, 2-ethyl-3-methylbutyl, 1-propylbutyl,        1-(1-methylethyl)butyl and 1-(1-methylethyl)-2-methylpropyl        groups;    -   the term “a cycloalkyl group” is intended to mean: cyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,        bicyclo[2.2.1]heptyl, cyclooctyl, bicyclo[2.2.2]octyl,        bicyclo[3.2.1]octyl, adamantyl.

The compounds of formula (I) are prepared by reaction between a compoundof formula (II):

in which R₁ and Ar₂ are as defined for (I), and an amine of formulaAr′₁NH₂ (III) in which Ar′₁ is Ar₁, as defined for (I) or a precursor ofAr₁; where appropriate, the Ar′₁ group of the compound thus obtained isconverted to an Ar₁ group.

In accordance with the invention, the compounds of formula (I) can beprepared according to a process characterized in that the following arereacted:

-   -   (i) a compound of formula:

in which R₁₀ is a leaving group such as: (a) halogen, in particular Clor Br, or (b) alkyl-S(O)m- with m=0, 1, or 2; R₁₁ is NHC(O)—NH—R₁; and

-   -   (ii) an amine of formula Ar′₁NH₂ (III) in which Ar′₁ is Ar₁ as        defined for (I) or a precursor of Ar₁; where appropriate, the        Ar′₁ group of the compound thus obtained is converted to an Ar₁        group.

When R₁₀ is halogen or alkyl-S(O)m-, with m=2, the reaction is carriedout in a solvent, preferably a polar solvent:

-   -   (i) for example tetrahydrofuran, dimethyl sulphoxide or ethanol,        optionally in the presence of a trace of acid such as        hydrochloric acid; or    -   (ii) in dimethyl sulphoxide in the presence of a strong base        such as tBuOK; at a temperature between ambient temperature and        the reflux temperature of the solvent.

When R₁₀ is alkyl-S(O)m- with m=0 or 1, the reaction can be carried outwith Ar′₁NH₂ (III) in the molten state, preferably at a temperature inthe region of 200° C., without catalyst.

Where appropriate, the amine functions present in the Ar′₁ group ofcompound (III) are salified or protected beforehand.

The compounds of formula (II) are prepared by following the proceduredescribed in European patent 790 997 and U.S. Pat. No. 5,733,913, asdescribed in scheme 1 below:

mCPBA: meta-chloroperbenzoic acid.

The amines of formula (III) Ar′₁NH2 are known or prepared by knownmethods from the corresponding nitrated derivatives Ar′₁NO₂ (IV), byreduction either (i) in an acidic medium in the presence of a metal suchas powdered zinc or iron, or (ii) by hydrogen in the presence of acatalyst such as Pd/C. Ar′ is Ar or a precursor of Ar.

The compounds of formula (IV) are known or prepared by known methods.

The compounds according to the invention are obtained in racemic form;the optically pure isomers can then be prepared using resolving methodsknown to those skilled in the art, such as crystallization by formationof salts with chiral agents. Compounds according to the invention inoptically pure form can also be prepared using methods of asymmetric orstereospecific synthesis, the use of chromatographic techniques using achiral phase. Moreover, the products of the invention can be separatedvia the formation of diastereoisomers, separation thereof, and then thedecomposition of the pharmaceutically useful diastereoisomer into itsenantiomerically pure active product. Enzymatic techniques can also beused. Additional known separating techniques can be used. They includethose disclosed in: Enantiomers, Racemates, and Resolutions, John Wileyand Sons, New York (1981).

The compounds according to the invention can also be prepared in a formenriched in one stereoisomer as soon as there is preparation of thesynthesis intermediates. Thus, the resolving of the enantiomers of theamines of formula (III) or of the nitrated precursors (IV) can becarried out by one of the abovementioned methods.

The following examples describe the preparation of certain intermediatesand of compounds in accordance with the invention. These examples arenot limiting and merely illustrate the present invention.

In the examples, the following abbreviations are used:

-   Boc: tert-butoxycarbonyl-   BOP: benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluorophosphate-   THF: tetrahydrofuran-   AT: ambient temperature-   TFA: trifluoroacetic acid-   DCM: dichloromethane-   DMSO: dimethyl sulphoxide-   DMF: dimethylformamide-   MeOH: methanol-   DCCI: dicyclohexylcarbodiimide-   DIPEA: diisopropylethylamine-   KHSO₄/K₂SO₄: 5% solution of KHSO₄/K₂SO₄.

The proton nuclear magnetic resonance (NMR) spectra are recorded at 200or 250 MHz in DMSO-d₆, unless otherwise indicated. The DMSO-d₆ signal isat 2.5 ppm and serves as a reference. For the interpretation of thespectra, the following abbreviations are used: s: singlet, d: doublet,t: triplet, m: unresolved peak, mt: multiplet, bs: broad singlet, dd:doublet of a doublet, qd: quadruplet, qt: quintuplet.

Mp: melting point (in degrees Celsius) as measured on a Büchi B545apparatus with a temperature gradient of 1° C. per minute.

MH+: Mass spectrum. The compounds are analyzed by HPLC—UV—MS (liquidchromatography—UV detection—mass spectrometry) coupling. The deviceused, sold by Agilent, is composed of an HP1100 chromatograph equippedwith an Agilent diode array detector and an MSD Quad quadripolar massspectrometer.

The analytical conditions are as follows:

-   Column: C 18 Symmetry (50×2.1 mm; 3.5 μm)-   Eluent A: H₂O+0.005% TFA at pH 3.15-   Eluent B: CH₃CN+0.005% TFA-   Gradient:

Time (min) % B 0 0 10 90 15 90 16 0 20 0 Column temperature: 30° C. Flowrate: 0.4 ml/min Detection: λ = 210 nm tr: retention time v: volume.

Preparation of a Compound of Formula (II)

Preparation 1

N-(t-Butyl)-N′-[6-(2,6-dichlorophenyl)-2-(methylsulphonyl)pyrido[2,3-d]pyrimidin-7-yl]urea

1.1 Ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate

140 ml of a 20% NH₄OH solution are added, in 20 minutes, and whilemaintaining the temperature at around 20° C., to a suspension of 50.7 gof ethyl 4-chloro-2-(methylthio)pyrimidin-5-carboxylate in 400 ml ofEtOH. After stirring at ambient temperature for 20 hours, the reactionmedium is concentrated under vacuum almost to dryness, and the residueis then taken up in 350 ml of water, stirred for 20 minutes, filtered,washed with 3×60 ml of water, and then dried under vacuum in thepresence of P₂O₅. A white solid is obtained, Mp=134-135° C., m=39.9 g.

1.2 [4-Amino-2-(methylthio)pyrimidin-5-yl]methanol

210 ml of a 1M solution of LiAlH₄ in THF are added, in 45 minutes, whilemaintaining the temperature below 30° C., to 39.68 g of ester obtainedin the previous stage dissolved in 1 litre of THF. The mixture isstirred for a further hour and the temperature is then decreased to 5°C. and 9 ml of water, 6.5 ml of 5N sodium hydroxide and then 32 ml ofwater are successively added dropwise. After stirring for 10 minutes,the solid is filtered off and then rinsed with THF. The filtrate isconcentrated to dryness under vacuum and the residue is then redissolvedin 600 ml of boiling toluene, the product is rapidly filtered under hotconditions in order to remove some of the insoluble material and thefiltrate is left to cool overnight. The white crystals obtained arefiltered, washed with a small amount of toluene and then of ether anddried, Mp=124-127° C., m=23.9 g.

1.3 4-Amino-2-(methylthio)pyrimidine-5-carbaldehyde

79.5 g of active MnO₂ are added, in 2 minutes, to a suspension of 23.8 gof the alcohol obtained in the previous stage in 1600 ml of chloroform,and the mixture is stirred at ambient temperature overnight; the solidis filtered off, and washed with 3×75 ml of CHCl₃, and the filtrate isconcentrated to dryness under vacuum; the white solid residue is takenup in ether, filtered and dried, Mp=184-186° C., m=21.05 g.

1.4 6-(2,6-Dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-amine

5.47 g of 60% NaH are added, in 5 minutes, to 21 g of the aldehydeobtained in the previous stage, dissolved in 240 ml of DMF and cooled to5° C., followed by 29.05 g of 2,6-dichlorophenylacetonitrile, in 20minutes, in small fractions. The stirring is continued for 30 minutes at5° C. and then at ambient temperature overnight. The reaction medium iscooled to 5° C. and 65 ml of a saturated NH₄Cl solution and then 500 mlof a water/ice mixture are added; a red precipitate forms, which isfiltered off, washed twice with water, filter-dried to a maximum, andwashed with ether, with 100 ml of chloroform and then with ether again;after drying, a beige solid is obtained, Mp=250-253° C., m=29.92 g.

The ether and chloroform washing phases are concentrated to dryness, andthe product is taken up in a small amount of chloroform, to which etheris added: a second cast of 3.15 g is obtained, total m=33.07 g.

1.5N-(t-Butyl)-N′-[6-(2,6-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl]urea

4.6 g of 60% NaH are added, in 10 minutes and while maintaining thetemperature below 25° C., to 29.9 g of the amine obtained above insolution in 300 ml of DMF; the mixture is stirred for a further 20minutes and then 12.2 ml of tert-butyl isocyanate are added in 20minutes and the mixture is stirred overnight. The reaction medium ispoured slowly onto 800 ml of a water/ice mixture+100 ml of 6N HCl; theprecipitate formed is filtered, washed with water, filter-dried, andthen stirred for 1 hour in 300 ml of ether, then filtered, washed withether and dried. A beige solid is obtained, Mp=195-196° C. (decomp.),m=26.5 g.

1.6N-(t-Butyl)-N′-[6-(2,6-dichlorophenyl)-2-(methylsulphonyl)pyrido[2,3-d]pyrimidin-7-yl]urea

27 g of meta-chloroperbenzoic acid (77%) are added, in 25 minutes andwhile maintaining the temperature below 25° C., to 21.95 g of ureaobtained above in solution in 300 ml of chloroform. A precipitate forms.After 2 hours, the reaction medium is diluted with 1 litre ofdichloromethane and Na₂SO₄ followed by 14 g of Ca(OH)₂ are added. Afterstirring for 30 minutes, the solid is filtered off and washed withdichloromethane and the filtrate is then concentrated to dryness. Theresidue is triturated in 80 ml of ether under hot conditions; theproduct is left to cool, and the white solid is then filtered off,washed with ether and dried, Mp=138-140° C., m=20.5 g.

In the same manner as for the compound described in preparation 1, thecompounds of formula (II) below can be prepared:

TABLE 1 Prep. Ar2 R1 NMR 1 2,6-dichloro- tert- 1.40: s: 9H; 3.50: s: 3H;7.50-7.70: phenyl butyl m: 3H; 8.55: s: 1H; 9.10: s: 1H; 9.60: s: 1H;9.95: s: 1H. 2 2,6-dichloro- phenyl 3.50 ppm: s: 3H; 7.10 ppm: t: 1H;phenyl 7.40 ppm: t: 2H; 7.55-7.75 ppm: m: 5H; 8.60 ppm: s: 1H; 9.60 ppm:s: 1H; 9.80 ppm: s: 1H; 11.90 ppm: s: 1H. 3 3,5-dimeth- tert- 1.40 ppm:s: 9H; 3.50 ppm: s: 3H; oxyphenyl butyl 3.80 ppm: s: 6H; 6.65-6.80 ppm:mt: 3H; 7.75 ppm: s: 1H; 8.45 ppm: s: 1H; 9.60 ppm: s: 1H; 9.80 ppm: s:1H. 4 2,6-dichloro- ethyl 1.20 ppm: t: 3H; 3.40 ppm: qd: 2H; phenyl 3.50ppm: s: 3H; 7.50 ppm-7.75 ppm: m: 3H; 8.55 ppm: s: 1H; 9.40 ppm: s: 1H;9.60 ppm: s: 1H; 9.70 ppm: s: 1H. 5 3,4-dimeth- tert- 1.40 ppm: s: 9H;3.45 ppm: s: 3H; oxyphenyl butyl 3.80 ppm: s: 3H; 3.90 ppm: s: 3H;7.10-7.20 ppm: m: 3H; 7.75 ppm: s: 1H; 8.45 ppm: s: 1H; 9.55 ppm: s: 1H;9.80 ppm: s: 1H. 6 phenyl tert- 1.40 ppm: s: 9H; 3.50 ppm: s: 3H; butyl7.60 ppm: bs: 6H; 8.45 ppm: s: 1H; 9.40 ppm: s: 1H; 9.80 ppm: s: 1H. 72-methoxy- tert- 1.40 ppm: s: 9H; 3.50 ppm: s: 3H; phenyl butyl 3.80ppm: s: 3H; 7.10-7.40 ppm: mt: 4H; 7.60 ppm: t: 1H; 8.40 ppm: s: 1H;9.60 ppm: s: 1H; 9.80 ppm: s: 1H. 8 2,6-dibromo- tert- 1.40 ppm: s: 9H;3.50 ppm: s: 3H; phenyl butyl 7.40 ppm: t: 1H; 7.85 ppm: d: 2H; 8.50ppm: s: 1H; 9.00 ppm: s: 1H; 9.60 ppm: s: 1H; 10.00 ppm: s: 1H. 92-bromo-6- tert- 1.40 ppm: s: 9H; 3.45 ppm: s: 3H; chlorophenyl butyl7.50 ppm: t: 1H; 7.65 ppm: d: 1H; 7.80 ppm: d: 1H; 8.50 ppm: s: 1H; 9.00ppm: s: 1H; 9.50 ppm: s: 1H; 9.90 ppm: s: 1H. 10 2,6-dibromo- ethyl 1.15ppm: t: 3H; 3.30 ppm: qd: 2H phenyl (masked by DOH); 3.50 ppm: s: 3H;7.40 ppm: t: 1H; 7.85 ppm: d: 2H; 8.50 ppm: s: 1H; 9.25 ppm: s: 1H; 9.60ppm: s: 1H; 9.70 ppm: s: 1H. 11 2-bromo-6- phenyl (DMSO + TFA) 3.55 ppm:s: 3H; 7.10 chlorophenyl ppm: t: 1H; 7.30-7.90 ppm: m: 7H; 8.60 ppm: s:1H; 9.65 ppm: s: 1H. 12 2,6-dibromo- phenyl 3.55 ppm: s: 3H; 7.10 ppm:t: 1H; phenyl 7.35 ppm: qd: 3H; 7.60 ppm: d: 2H; 7.85 ppm: d: 2H; 8.60ppm: s: 1H; 9.70 ppm: s: 1H; 9.80 ppm: s: 1H; 12.00 ppm: s: 1H. 132,4-dichloro- tert- 1.35 ppm: s: 9H; 3.50 ppm: s: 3H; phenyl butyl7.45-7.60 ppm: mt: 2H; 7.80 ppm: s: 1H; 8.40 ppm: s: 1H; 8.80 ppm: s:1H; 9.55 ppm: s: 1H; 9.80 ppm: s: 1H. 14 2,6-dimethyl- tert- 1.40 ppm:s: 9H; 2.00 ppm: s: 6H; phenyl butyl 3.50 ppm: s: 3H; 7.10 ppm: s: 1H;7.25-7.45: m: 3H; 8.45 ppm: s: 1H; 9.60 ppm: s: 1H; 9.80 ppm: s: 1H. 152,6-difluoro- tert- 1.40 ppm: s: 9H; 3.50 ppm: s: 3H; phenyl butyl7.25-7.40: mt: 2H; 7.55-7.70 ppm: mt: 1H; 8.65 ppm: s: 1H; 9.20 ppm: s:1H; 9.60 ppm: s: 1H; 9.75 ppm: s: 1H. 16 2,6-dichloro- iso- 1.20 ppm: d:6H; 3.50 ppm: s: 3H; phenyl propyl 3.85-4.00 ppm: mt: 1H; 7.50-7.70 ppm:m: 3H; 8.50 ppm: s: 1H; 9.25 ppm: s: 1H; 9.65 ppm: s: 1H; 9.75 ppm: bs:1H.

Preparation of the Compounds of Formula (III)

The preparation numbers used refer to the numbers of the compounds inTable 2 hereinafter.

Preparations 17 and 18 Commercial product.

Preparation 19 Prepared according to J. Hetero. Chem. 1986, 23,1645-1649 and isolated in hydrochloride form.

Preparation 20

Prepared according to J. Chem. Soc. 1928, 121.

Preparation 21

2.27 g of NaBH₄ are added, in small portions over a period of 8 hours,to 1.12 g of ethyl 5-nitrobenzo[b]furan-2-carboxylate in 50 ml of THF,and the mixture is then stirred for 40 hours. 5 ml of methanol and then5 ml of water are added. The reaction medium is extracted with EtOAc,and the organic phase is washed with water, with a 5% KHSO₄/K₂SO₄solution, with water, and then with a saturated NaCl solution. Afterdrying and concentration under reduced pressure, 0.74 g of the expectedproduct are recovered in solid form.

730 mg of the product obtained in stage 21.1 are dissolved in 9 ml ofDCM and maintained at 5° C. 1 ml of triethylamine is added at 5° C., andthen 536 mg of methanesulphonyl chloride are added in 15 minutes. Thetemperature is maintained at 5° C. for 15 minutes, and the reactionmedium is then allowed to return to ambient temperature for 55 minutes.The reaction medium is then diluted with DCM and water. The organicphase is separated by settling out, washed with water and with asaturated NaCl solution, dried and evaporated under reduced pressure.0.98 g of oil, comprising a mixture of mesylate (expected product) andof chloride (product from substitution of the CH₂OH in the 2-position ofbenzo[b]furan with CH₂Cl), is obtained.

0.97 g of the product obtained in stage 21.2, in 10 ml of DMF, aretreated with 1.05 g of diethylamine for 18 hours. The reaction medium isextracted with EtOAc, the organic phase is washed with water and with asaturated NaCl solution and dried, and the solvents are then evaporatedoff under reduced pressure. 0.93 g of oil is obtained.

4.48 g of powdered Zn are added to 1.16 g of product obtained in stage21.3 in 40 ml of THF, followed, at −5° C., by 5 ml of acetic acid, overa period of 25 minutes.

After 1 h 15 of reaction, the residual solid is eliminated from thereaction medium by filtration, the solid is washed with a small amountof THF, and the organic phases are combined, diluted with EtOAc andwater, and then brought to pH=9 with 10N NaOH. After separation bysettling out, the organic phase is isolated and washed with a 15% Na₂CO₃solution, with water and with a saturated NaCl solution, dried andevaporated. 900 mg of oil are obtained.

Preparation 22

1.26 g of sodium azide are added to 1.64 g of2-chloromethyl-5-nitrobenzoxazole (prepared according to Synth.Communications 1989, 19, 2921-2924) in 25 ml of DMF and the mixture isstirred at ambient temperature overnight. The reaction medium is pouredonto 150 ml of EtOAc and washed twice with ice-cold water and then witha saturated NaCl solution. The organic phase is dried and concentratedunder reduced pressure. 1.42 g of black oil are recovered.

2.84 g of triphenylphosphine are added, in 10 minutes to 1.40 g of theproduct obtained in stage 22.1 in 30 ml of EtOAc, and then, after 10minutes, 1.16 ml of water are added in 2 minutes. After 24 hours withstirring at 60° C., and then cooling, the reaction medium is dilutedwith EtOAc, and the organic phase is washed with water and then with asaturated NaCl solution. The organic phase is dried and concentratedunder reduced pressure. The residue is taken up in Et₂O and is extractedtwice with 1N HCl. The acid phases are combined, brought into contactwith EtOAc, and brought to pH=10 with 10N NaOH. After separation bysettling out, the organic phase is washed with water and then with asaturated NaCl solution. The organic phase is dried and concentratedunder reduced pressure, to give 468 mg of the expected product in theform of an oil.

The product obtained in stage 22.2 is dissolved in 10 ml of DCM, andthen 0.4 equivalent of triethylamine followed by 1.1 equivalents ofBOC₂O are added. After 5 h, the reaction medium is diluted with CH₂Cl₂and then washed successively with a 5% KHSO₄/K₂SO₄ solution, water and asaturated NaCl solution. The crude is dried and evaporated under reducedpressure, so as to obtain 388 mg of the expected product.

The product obtained in stage 19.3 is reduced quantitatively withZn/AcOH, so as to obtain an oil, according to the method described inpreparation 18.4.

Preparation 23

23.1 Prepared according to J. Hetero. Chem. 1973, 10, 755.

23.2 Reduction of the product obtained in stage 23.1 with Sn/HBr inwater according to Chem.Abstr. 1950, 4474.

Preparation 24 Prepared according to J. Hetero. Chem. 1970, 7,1019-1027.

Preparation 25 Prepared according to Boll. Sci. Fac. Chim. Ind. Bologna1964 vol. 22 pages 33-37

Preparation 26

Prepared according to the procedure described in patent applicationWO92/05164.

The compounds of formula (III) are characterized in Table 2 below:

TABLE 2 Preparations of the compounds of formula (III). X = NO₂ (IV),HCl X = NH₂ (III) Prep. Ar₁ NMR NMR 17

— Commercial product 18

— Commercial product 19

— Prepared according to J.Hetero. Chem. 1986,23, 1645-1649 andisolatedinhydrochloride form 20

— Prepared according toJ. Chem. Soc. 1928, 121 21

21.31.00 ppm: t: 6 H; 2.50ppm: qd: 4 H; 3.75ppm: s: 2 H; 7.00 ppm:s: 1H; 7.75 ppm: d:1 H; 8.15 ppm: d: 1 H;8.50 ppm: d: 1 H. 21.41.00 ppm: t:6 H; 2.55ppm: qd: 4 H; 3.65 ppm:s: 2 H; 4.90 ppm: bs:2 H; 6.45 ppm: s: 1H;6.50 ppm: dd: 1 H; 6.65ppm: d: 1 H; 7.15 ppm:d: 1 H. 22

22.31.40 ppm: s: 9 H; 4.45ppm: d: 2 H; 7.65 ppm:t: 1 H; 7.95 ppm: d:1 H;8.30 ppm: dd: 1 H;8.60 ppm: d: 1 H. 22.41.35 ppm: s: 9 H; 4.25ppm: d: 2H; 4.95: bs:2 H; 6.55 ppm: dd: 1 H;6.75 ppm: d: 1 H; 7.25ppm: d: 1 H;7.45 ppm:t: 1 H. 23

23.1Prepared according toJ. Hetero. Chem. 1973,10, 755 23.2Preparedaccording toChem. Abstr. 1950,4474. 24

— Prepared according to J.Hetero. Chem. 1970, 7,1019-1027 25

— Prepared according toBoll. Sci. Fac. Chim.Ind. Bologna 1964vol. 22pages 33-37 26

— Prepared according tothe procedure describedin patentapplicationWO92/05164

The numbers of the compounds exemplified refer to those given in Table 3hereinafter, which illustrates the chemical structures and the physicalproperties of some compounds according to the invention. When theycontain an asymmetrical carbon, these compounds are obtained in racemicform.

EXAMPLE 1 (Compound No. 1)N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)urea

3.21 g (28.6 mmol) of t-BuOK are added, in 15 minutes, to 3.32 g (20mmol) of the amine of preparation 17 in Table 2, in 45 ml of DMSO, andthen 7.71 g (16.5 mmol) of the urea of preparation 1 in Table 1 areadded in 20 minutes. 1 g of t-BuOK is again added after 2 hours, andthen 1 g of t-BuOK is again added after 2 hours. After reaction for 6hours, the reaction medium is diluted with ice-cold water, and thenextracted with EtOAc. The organic phase is washed twice with water andonce with a saturated NaCl solution, dried and concentrated underreduced pressure. The crude is triturated in an Et₂O/heptane mixture,and the precipitate is filtered off and then chromatographed on silicagel, the eluent being 88/12 (v/v) CHCl₃/EtOAc. 5 g of expected productare obtained. MH⁺=539.

EXAMPLE 2 (Compound No. 2)N-[2-(2,1,3-benzothiadiazol-4-ylamino)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)urea

Compound 2 is prepared in the same way as compound 1, starting with theamine of preparation 18 in Table 2.

EXAMPLE 3 (Compound No. 3)N-[6-(2,6-dichlorophenyl)-2-[(1,3-dihydro-2,2-dioxido-2,1-benzisothiazol-5-yl)amino]pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)urea

A mixture of 437 mg of the amine of preparation 19 in Table 2, inhydrochloride form, and of 750 mg of the urea of preparation 1 in Table1, are heated in 15 ml of ethanol for 5 hours. The reaction medium isevaporated to dryness and then taken up in 50 ml of CHCl₃ and 20 ml of asaturated NaHCO₃ solution. The organic phase is separated by settlingout, and washed with water and then with a saturated NaCl solution. Theorganic phase is dried and saturated under reduced pressure. The residueis purified by flash chromatography with a gradient of 0 to 20% (v/v) ofEtOAc in chloroform. 275 mg of a yellow solid are obtained. MH⁺: 572.

EXAMPLE 4 (Compound No. 4)N-[6-(2,6-dichlorophenyl)-2-[(2-methyl-6-benzoxazolyl)amino]pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)urea

210 mg of the amine of preparation 20 in Table 2 and 562 mg of the ureaof preparation 1 in Table 1 are heated for 8 hours at 45° C. in 20 ml ofethanol containing 0.02 ml of concentrated HCl. After concentrationunder reduced pressure, the residue is chromatographed on silica gel,the eluent being CHCl₃/MeOH: 98/2 (v/v). 300 mg of product in the formof a yellow solid are isolated. MH⁺: 536.

EXAMPLE 5 (Compound No. 5)N-[6-(2,6-dichlorophenyl)-2-[[2-[(diethylamino)methyl]-5-benzofuranyl]amino]pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)urea

Compound 5 is prepared in the same way as compound 4, starting from theamine 21.4 of preparation 21 in Table 2.

EXAMPLE 6 Compound No. 6 1,1-dimethylethyl[[5-[[6-(2,6-dichlorophenyl)-7-[[[(1,1-dimethylethyl)amino]carbonyl]amino]pyrido[2,3-d]pyrimidin-2-yl]amino]-2-benzoxazolyl]methyl]carbamate

Compound 6 is prepared in the same way as compound 4, starting from theamine 22.4 of preparation 22 in Table 2.

EXAMPLE 7 (Compound No. 7)N-[2-[[2-(aminomethyl)-5-benzoxazolyl]amino]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)urea

190 mg of compound 6 are treated for 1 hour with 3 ml of TFA in 2 ml ofDCM. After concentration under reduced pressure, the residue is taken upin a DCM/water mixture and the pH is then brought to 9 by adding a 15%Na₂CO₃ solution. After separation by settling out, the organic phase iswashed with water and then with a saturated NaCl solution, dried, andconcentrated under reduced pressure. The crude is purified by flashchromatography on silica gel, the eluant being 0 to 10% (v/v) ofmethanol in DCM. 100 mg of yellow solid are isolated. MH⁺: 551.

EXAMPLE 8 (Compound No. 8)N-[6-(2,6-dichlorophenyl)-2-(imidazo[1,2-a]pyridin-6-ylamino)pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)urea

Compound 8 is prepared in the same way as compound 4, starting from theamine 23.2 of preparation 23 in Table 2.

EXAMPLE 9 (Compound No. 9)N-[6-(2,6-dichlorophenyl)-2-([1,2,4]triazolo[1,5-a]pyridin-6-ylamino)pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)urea

Compound 9 is prepared in the same way as compound 4, starting from theamine of preparation 24 in Table 2.

EXAMPLE 10 (Compound No. 10)N-[2-(2,1,3-benzoxadiazol-5-ylamino)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)urea

0.168 g of tBuOK is added in 25 minutes, to a mixture of 0.468 g of theproduct of preparation 1 and 0.202 g of the amine (III) of preparation25 in Table 2, in 6 ml of DMSO, and then a further 0.168 g is added in 1hour. After stirring for 2 hours, the reaction medium is extracted withethyl acetate which is washed successively with water and a saturatedNaCl solution. After drying over Na₂SO₄ and evaporation of the ethylacetate, the crude product is purified by flash chromatography on silicagel with a gradient of 0 to 8% (v/v) of ethyl acetate indichloromethane. A beige powder is obtained, m=0.22 g. MH+=523.

EXAMPLE 11 (Compound No. 11)N-[2-(1,3-dihydro-2,2-dioxido-2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)urea

Compound 11 is prepared in the same way as compound 4, starting from theamine of preparation 26 in Table 2.

EXAMPLES 12-21 Compounds No. 12-21

Compounds 12-21 are prepared in the same way as compound 1, startingfrom the amine (III) of preparation 17 in Table 2 and an appropriateurea selected from the products of formula (II) of the preparations inTable 1.

EXAMPLE 12 (Compound No. 12)N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2-bromo-6-chlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)ureaEXAMPLE 13 (Compound No. 13)N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-ethylureaEXAMPLE 14 (Compound No. 14)N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-dibromophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)ureaEXAMPLE 15 (Compound No. 15)N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-dibromophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-ethylureaEXAMPLE 16 (Compound No. 16)N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-phenylureaEXAMPLE 17 (Compound No. 17)N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)ureaEXAMPLE 18 (Compound No. 18)N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-phenylpyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)ureaEXAMPLE 19 (Compound No. 19)N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-dimethylphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)ureaEXAMPLE 20 (Compound No. 20)N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-difluorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)ureaEXAMPLE 21 (Compound No. 21)N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-(1-methylethyl)urea

Tables 3 and 4 below illustrate the chemical structures and the physicalproperties of some examples according to the invention. In these tables,Me, Et, iPr and tBu are, respectively, methyl, ethyl, isopropyl andtert-butyl groups, and Boc (or BOC) is the tert-butoxycarbonyl group.

TABLE 3 (I)

NMR Compounds Ar₁ characterization 1

1.50 ppm: s: 9 H; 7.50-7.70 ppm: m: 3 H;7.95 ppm: dd: 2 H; 8.15 ppm: s:1 H; 8.35ppm: s: 1 H; 9.20 ppm: s: 1 H; 9.35 pmm:s: 1 H; 10.65 ppm: s: 1H; 10.75 ppm: s:1 H. 2

1.40 ppm: s: 9 H; 7.45-7.80 ppm: m: 5 H;8.15 ppm: s: 1 H; 8.35 ppm: s: 1H; 8.80ppm: d: 1 H; 9.20 ppm: s: 1 H; 9.55 pmm:s: 1 H; 10.60 ppm: s: 1H. 3

1.45 ppm: s: 9 H; 4.45 ppm: s: 2 H; 6.75ppm: d: 1 H; 7.45-7.70 ppm: m: 3H; 7.80ppm: de: 1 H; 8.05 ppm: s: 1 H; 8.15 ppm:bs: 2 H; 9.05 ppm: s: 1H; 10.10 ppm: s:1 H; 10.20-10.30 ppm: bs: 1 H; 10.60ppm: s: 1 H. 4

1.45 ppm: s: 9 H; 2.60 ppm: s: 3 H; 7.50-7.70ppm: m: 5 H; 8.10 ppm: s: 1H; 8.30ppm: bs: 1 H; 8.90 ppm: bs: 1 H; 9.15 ppm:s: 1 H; 10.45 ppm: s: 1H; 10.75 ppm: s:1 H. 5

1.00 ppm: t: 6 H; 1.45 ppm: s: 9 H; 2.50ppm: qd: 4 H; 3.70 ppm: s: 2 H;6.55 ppm:s: 1 H; 7.40-7.70 ppm: m: 5 H; 8.10 ppm:s: 2 H; 8.55 ppm: bs: 1H; 9.10 ppm: s: 1 H;10.15 ppm: s: 1 H; 10.65 ppm: s: 1 H. 6

1.30 ppm: s: 9 H; 1.40 ppm: s: 9 H; 4.35ppm: d: 2 H; 7.45-7.60 ppm: m: 5H; 7.75ppm: dd: 1 H; 8.05 ppm: s: 1 H; 8.10 ppm:bs: 1 H; 8.65 ppm: s: 1H; 9.10 ppm: s: 1 H;10.30 ppm: s: 1 H; 10.60 ppm: s: 1 H. 7

1.45 ppm: s: 9 H; 2.10 ppm: bs: 2 H; 3.90ppm: s: 2 H; 7.45-7.70 ppm: m:4 H; 7.80ppm: dd: 1 H; 8.05 ppm: s: 1 H; 8.15 ppm:bs: 1 H; 8.65 ppm: s:1 H; 9.10 ppm: s: 1 H;10.25 ppm: s: 1 H; 10.70 ppm: s: 1 H. 8

1.50 ppm: s: 9 H; 7.40-7.70 ppm: m: 7 H;8.10 ppm: s: 1 H; 8.20 ppm: s: 1H; 9.10ppm: s: 1 H; 9.65 ppm: s: 1 H; 10.30 ppm:s: 1 H; 10.60 ppm: s: 1H. 9

1.50 ppm: s: 9 H; 7.45-7.70 ppm: m: 3 H;7.85 ppm: s: 2 H; 8.15 ppm: s: 1H; 8.25ppm: d: 1 H; 8.40 ppm: s: 1 H; 9.15 ppm: s:1 H; 10.10 pmm: s: 1H; 10.55 ppm: s: 1 H;10.60 ppm: s: 1 H. 10

1.45 ppm: s: 9 H; 7.50-7.70 ppm: mt:3 H; 7.75 ppm: d: 1 H; 8.00 ppm: d:1H; 8.20 ppm: s: 1 H; 8.40 ppm: s: 1 H;9.15 ppm: s: 1 H; 9.25 ppm: s: 1H;10.65 ppm: s: 1 H; 10.90 ppm: s: 1 H. 11

1.45 ppm: s: 9 H; 6.65 ppm: d: 1 H;7.40 ppm: s: 1 H; 7.45-7.70 ppm: m:4H; 8.05 ppm: s: 2 H; 9.05 ppm: s: 1 H;10.00 ppm: s: 1 H; 10.55 ppm: s: 1H;10.75 ppm: bs: 2 H.

TABLE 4 (I)

Com- NMR pound R1 Ar2 characterization 12 tert-butyl 2-bromo-6- 1.50ppm: s: 9 H; 7.45 ppm: chlorophenyl t: 1 H; 7.65 ppm: d: 1 H; 7.80 ppm:d: 1 H; 8.00 ppm: dd: 2 H; 8.15 ppm: s: 1 H; 8.25 ppm: s: 1 H; 9.20 ppm:s: 1 H; 9.30 ppm: s: 1 H; 10.75 ppm: s: 1 H; 10.85 ppm: s: 1 H. 13 ethyl2,6-dichlorophenyl (DMSO + TFA deuterated) 1.15 ppm: t: 3 H; 3.35 ppm:qd: 2 H; 7.50-7.70 ppm: m: 3 H; 8.00 ppm: dd: 2 H; 8.45 ppm: s: 1 H;9.00 ppm: s: 1 H; 9.30 ppm: s: 1 H. 14 tert-butyl 2,6-dibromophenyl 1.50ppm: s: 9 H; 7.35 ppm: t: 1 H; 7.80 ppm: d: 2 H; 8.00 ppm: dd: 2 H; 8.15ppm: s: 2 H; 9.15 ppm: s: 1 H; 9.30 ppm: s: 1 H; 10.75 ppm: s: 1 H;10.85 ppm: s: 1 H. 15 ethyl 2,6-dibromophenyl 1.30 ppm: t: 3 H; 3.30ppm: qd: 2 H; 7.35 ppm: t: 1 H; 7.80 ppm: d: 2 H; 8.00 ppm: dd: 2 H;8.15 ppm: s: 1 H; 8.50 ppm: s: 1 H; 9.15 ppm: s: 1 H; 9.20 ppm: s: 1 H;10.20 ppm: s: 1 H; 10.70 ppm: s: 1 H. 16 phenyl 2,6-dichlorophenyl 7.15ppm: t: 1 H; 7.50-7.70 ppm: mt: 5 H; 7.75-8.10 ppm: mt: 4 H; 8.30 ppm:s: 1 H; 9.25 ppm: s: 1 H; 9.35 ppm: s: 1 H; 9.50 ppm: s: 1 H; 10.85 ppm:s: 1 H; 13.30 ppm: s: 1 H. 17 tert-butyl 3,5- 1.50 ppm: s: 9 H; 3.70ppm: dimethoxyphenyl s: 6 H; 6.65 ppm: s: 3 H; 7.30 ppm: s: 1 H; 8.00ppm: dd: 2 H; 8.20 ppm: s: 1 H; 9.20 ppm: s: 1 H; 9.30 ppm: s: 1 H;10.50 ppm: s: 1 H; 10.70 ppm: s: 1 H. 18 tert-butyl phenyl 1.50 ppm: s:9 H; 7.25 ppm: s: 1 H; 7.45-7.65 ppm: m: 5 H; 8.00 ppm: dd: 2 H; 8.20ppm: s: 1 H; 9.20 ppm: s: 1 H; 9.35 ppm: s: 1 H; 10.50 ppm: s: 1 H;10.75 ppm: s: 1 H. 19 tert-butyl 2,6- 1.45 ppm: s: 9 H; 2.00 ppm:dimethylphenyl s: 6 H; 6.55 ppm: s: 1 H; 7.20-7.40: m: 3 H; 7.95 ppm:dd: 2 H; 8.10 ppm: s: 1 H; 9.15 ppm: s: 1 H; 9.30 ppm: s: 1 H; 10.45ppm: s: 1 H; 10.65 ppm: s: 1 H. 20 tert-butyl 2,6-difluorophenyl 1.45ppm: s: 9 H; 7.15-7.30: mt: 2 H; 7.50-7.70 ppm: mt: 1 H; 7.95 ppm: dd: 2H; 8.25 ppm: s: 1 H; 8.45 ppm: s: 1 H; 9.15 ppm: s: 1 H; 9.30 ppm: s: 1H; 10.50 ppm: s: 1 H; 10.70 ppm: s: 1 H. 21 isopropyl 2,6-dichlorophenyl1.35 ppm: d: 6 H; 3.80-4.00 ppm: mt: 1 H; 7.40-7.55 ppm: mt: 1 H;7.60-7.65 ppm: mt: 2 H; 7.95 ppm: dd: 2 H; 8.15 ppm: s: 1 H; 8.60 ppm:s: 1 H; 9.15 ppm: s: 1 H; 9.25 ppm: s: 1 H; 10.45 ppm: d: 1 H; 10.75ppm: s: 1 H.

The compounds according to the invention were subjected topharmacological assays for determining their anticancer activity.

The compounds of formula (I) according to the present invention weretested in vitro on a panel of tumour lines of human origin, originating:

-   -   from breast cancer: MDA-MB231 (American Type culture collection,        Rockville, Md., USA, ATCC-HTB26), MDA-A1 or MDA-ADR (called        multi-drug resistant MDR line, and described by E. Collomb et        al., in Cytometry, 12(1):15-25, 1991), and MCF7 (ATCC-HTB22),    -   from prostate cancer: DU145 (ATCC-HTB81) and PC3 (ATCC-CRL1435),    -   from colon cancer: HCT116 (ATCC-CCL247) and HCT15 (ATCC-CCL225),    -   from lung cancer: H460 (described by Carmichael in Cancer        Research 47 (4):936-942, 1987 and provided by the National        Cancer Institute, Frederick Cancer Research and Development        Center, Frederick, Md., USA),    -   from glioblastoma: SF268 (described by Westphal in Biochemical &        Biophysical Research Communications 132 (1): 284-289, 1985 and        provided by the National Cancer Institute, Frederick Cancer        Research and Development Center, Frederick, Md., USA),    -   from leukaemia: CMLT1 (described by Kuriyama et al. in Blood,        74: 1989, 1381-1387, by Soda et al. in British Journal of        Haematology, 59: 1985, 671-679 and by Drexler, in Leukemia        Research, 18: 1994, 919-927 and provided by the company DSMZ        (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH)        Mascheroder Weg 1b, 38124 Braunschweig, Germany), K-562        (described by Lozzio et al., J Natl Cancer Inst 50: 535 (1973),        by Lozzio et al., Blood 45: 321 (1975), and provided by DSMZ No.        ACC 10), KG-1a (described by Koeffler et al., Blood 56: 265        (1980), and provided by DSMZ No. ACC 421), and Kasumi-1        (described by Asou et al., Blood 77: 2031 (1991), and provided        by DSMZ No. ACC 220).

The cell proliferation and viability were determined in a test using3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphophenyl)-2H-tetrazolium(MTS) according to Fujishita T. et al., Oncology, 2003, 64 (4), 399-406.In this test, the mitochondrial ability of the live cells to convert MTSto a coloured compound is measured after 72 hours of incubation of acompound of formula (I) according to the invention. The concentrationsof compound according to the invention which result in a 50% loss ofcell proliferation and cell viability (IC₅₀) are between 1 nM and 10 μM,depending on the tumor line and the compound tested. For example,compound No. 1 has an IC₅₀ of 40 nM on the K-562 line, an IC₅₀ of 50 nMon the KG-1a line and an IC₅₀ of 40 nM on the Kasumi-1 line. On theK-562 line, compound No. 5 has an IC₅₀ of 5 nM, compound No. 9 has anIC₅₀ of 19 nM, and compound No. 13 has an IC₅₀ of 74 nM. On the SF268,compound No. 7 has an IC₅₀ of 43 nM.

Thus, according to the present invention, it appears that the compoundsof formula (I) bring about a loss of proliferation and of viability ofthe tumour cells. It therefore appears that the compounds according tothe invention have an anticancer activity and an activity in thetreatment of other proliferative diseases such as psoriasis, restenosis,atherosclerosis or AIDS, for example, and also in diseases caused byvascular smooth muscle cell proliferation and in rheumatoid arthritis.

Thus, according to another of its aspects, a subject of the invention ismedicaments which comprise a compound of formula (I), or an additionsalt of the latter with a pharmaceutically acceptable acid or a hydrateor a solvate of the compound of formula (I).

These medicaments find their use in therapeutics, in particular in thetreatment or prevention of diseases caused or exacerbated by cellproliferation, and in particular tumour cell proliferation. A product inaccordance with the invention may be used for the manufacture of amedicament that is of use in the treatment of a pathological state, inparticular a cancer.

As an inhibitor of tumour cell proliferation, these compounds are of usein the prevention and treatment of leukaemias, both primary andmetastatic solid tumours, carcinomas and cancers, in particular: breastcancer; lung cancer; cancer of the small intestine, colon cancer andrectal cancer; cancer of the respiratory tracts, of the oropharynx andof the hypopharynx; (esophageal cancer; liver cancer, stomach cancer,cancer of the bile ducts, gall bladder cancer, pancreatic cancer; cancerof the urinary tracts, including kidney, urothelium and bladder; cancersof the female genital tract, including uterine cancer, cervical cancer,ovarian cancer, chloriocarcinoma and trophoblastoma; cancers of the malegenital tract, including prostate cancer, cancer of the seminalvesicles, testicular cancer, germinal cell tumours; cancers of theendocrine glands, including cancer of the thyroid, of the pituitarygland, of the adrenal glands; skin cancers, include hemangiomas,melanomas, sarcomas, including Kaposi's sarcoma; brain tumours, nervetumours, eye tumours, meningeal tumours, including astrocytomas,gliomas, glioblastomas, retinoblastomas, neurinomas, neuroblastomas,schwannomas, meningiomas; malignant hematopoietic tumours; leukaemias,(acute lymphocytic leukaemia (ALL), acute myeloid leukaemia (AML),chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL)),chloromas, plasmocytomas, T- or B-cell leukaemias, non-Hodgkin'slymphomas or Hodgkin's lymphomas, myelomas, various malignanthemopathies.

According to another of its aspects, the present invention relates topharmaceutical compositions comprising, as active ingredient, a compoundaccording to the invention. These pharmaceutical compositions contain aneffective dose of at least one compound according to the invention, or apharmaceutically acceptable salt, a hydrate or a solvate of saidcompound, and also at least one pharmaceutically acceptable excipient. Apharmaceutical composition can also contain, in addition, anotheranticancer ingredient.

Said excipients are selected according to the pharmaceutical form andthe method of administration desired, from the usual excipients whichare known to those skilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intratracheal, intranasal, transdermal or rectal administration, theactive ingredient of formula (I) above, or its optional salt, solvate orhydrate, can be administered in unit administration form, as a mixturewith conventional pharmaceutical excipients, to animals and to humanbeings for the prophylaxis or the treatment of the conditions ordiseases above.

Appropriate unit administration forms include the oral administrationforms such as tablets, soft or hard gelatin capsules, powders, granulesand oral solutions or suspensions, sublingual, buccal, intratracheal,intraocular and intranasal administration forms, forms of administrationby inhalation, topical, transdermal, subcutaneous, intramuscular orintravenous administration forms, rectal administration forms, andimplants. For topical application, the compounds according to theinvention can be used in creams, gels, ointments or lotions.

By way of example, a unit administration form of a compound according tothe invention in the form of a tablet can comprise the followingcomponents:

Compound according to the invention 50.0 mg Mannitol 223.75 mg Sodiumcroscarmellose 6.0 mg Corn starch 15.0 mg Hydroxypropylmethylcellulose2.25 mg Magnesium stearate 3.0 mg

The compounds of formula (I) above can be used at daily doses of 0.002to 2000 mg per kilogram of body weight of the mammal to be treated,preferably at daily doses of 0.1 to 300 mg/kg. In human beings, the dosecan range preferably from 0.02 to 10 000 mg per day, more particularlyfrom 1 to 3000 mg, depending on the age of the individual to be treatedor the type of treatment: prophylactic or curative.

There may be specific cases where higher or lower dosages areappropriate: such dosages do not depart from the scope of the invention.According to the usual practice, the dosage appropriate to each patientis determined by the physician according to the method ofadministration, and the weight and response of said patient.

According to another of its aspects, the present invention also relatesto a method of treatment of the pathologies indicated above, whichcomprises the administration, to a patient, of an effective dose of acompound according to the invention, or one of its pharmaceuticallyacceptable salts or hydrates or solvates.

According to the present invention, the compound(s) of formula (I) canbe administered in combination with one (or more) anticancer activeingredient(s), in particular antitumour compounds such as alkylatingagents, for instance alkylsulphonates (busulphan), dacarbazine,procarbazine, nitrogenous mustards (chlormethine, melphalan,chlorambucil), cyclophosphamide, ifosfamide; nitrosoureas such ascarmustine, lomustine, semustine, streptozocin; antineoplastic alkaloidssuch as vincristine, vinblastine; taxanes such as paclitaxel ortaxotere; antineoplastic antibiotics such as actinomycin; intercalatingagents, antineoplastic antimetabolites, folate antagonists,methotrexate; purine synthesis inhibitors; purine analogues such asmercaptopurine, 6-thioguanine; pyrimidine synthesis inhibitors,aromatase inhibitors, capecitabine, pyrimidine analogues such asfluorouracil, gemcitabine, cytarabine and cytosine arabinoside;brequinar; topoisomerase inhibitors such as camptothecin or etoposide;anticancer hormone agonists and antagonists including tamoxifen; kinaseinhibitors, imatinib; growth factor inhibitors; anti-inflammatories suchas pentosane polysulphate, corticosteroids, prednisone, dexamethasone;antitopoisomerases such as etoposide, anthracyclines includingdoxorubicin, bleomycin, mitomycin and methramycin; anticancer metalcomplexes, platinum complexes, cisplatin, carboplatin, oxaliplatin;interferon alpha, triphenylthiophosphoramide, altretamine;antiangiogenic agents; thalidomide; immunotherapy adjuvants; vaccines.

According to the present invention, the compounds of formula (I) canalso be administered in combination with one or more other activeingredients that are of use in one of the pathologies indicated above,for example an anti-emetic agent, pain-killer, anti-inflammatory, oranti-cachexia agent.

It is also possible to combine with the compounds of the presentinvention a radiation treatment. These treatments can be administeredsimultaneously, separately or sequentially. The treatment will beadapted by the practitioner according to the disease to be treated.

1. A compound according to formula (I):

wherein: R1 is tert-butyl and Ar2 is 2,6-dichlorophenyl; or R1 istert-butyl and Ar2 is 2-bromo-6-chlorophenyl; or R1 is ethyl and Ar2 is2,6-dichlorophenyl; or R1 is tert-butyl and Ar2 is 2,6-dibromophenyl; orR1 is ethyl and Ar2 is 2,6-dibromophenyl; or R1 is phenyl and Ar2 is2,6-dichlorophenyl; or R1 is tert-butyl and Ar2 is 3,5-dimethoxyphenyl;or R1 is tert-butyl and Ar2 is phenyl; or R1 is tert-butyl and Ar2 is2,6-dimethylphenyl; or R1 is tert-butyl and Ar2 is 2,6-difluorophenyl;or R1 is isopropyl and Ar2 is 2,6-dichlorophenyl; or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1, which is:

or a pharmaceutically acceptable salt thereof.
 3. A compound selectedfrom the group consisting of:N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2-bromo-6-chlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)urea;N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-ethylurea;N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-dibromophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)urea;N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-dibromophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-ethylurea;N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-phenylurea;N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)urea;N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-phenylpyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)urea;N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-dimethylphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)urea;N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-difluorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)urea;andN-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-(1-methylethyl)urea;or a pharmaceutically acceptable salt thereof.
 4. A pharmaceuticalcomposition comprising a compound according to claim 1 or apharmaceutically acceptable salt thereof; and at least onepharmaceutically acceptable excipient.
 5. A pharmaceutical compositioncomprising a compound according to claim 3 or a pharmaceuticallyacceptable salt thereof; and at least one pharmaceutically acceptableexcipient.
 6. A pharmaceutical composition comprising a compoundaccording to claim 2 or a pharmaceutically acceptable salt thereof; andat least one pharmaceutically acceptable excipient.